US5952000A - Fatty acid esters of lactic acid salts as permeation enhancers - Google Patents
Fatty acid esters of lactic acid salts as permeation enhancers Download PDFInfo
- Publication number
- US5952000A US5952000A US08/959,946 US95994697A US5952000A US 5952000 A US5952000 A US 5952000A US 95994697 A US95994697 A US 95994697A US 5952000 A US5952000 A US 5952000A
- Authority
- US
- United States
- Prior art keywords
- enhancer
- adhesive
- skin
- formula
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000003623 enhancer Substances 0.000 title claims abstract description 65
- -1 Fatty acid esters Chemical class 0.000 title claims abstract description 53
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 52
- 239000000194 fatty acid Substances 0.000 title claims abstract description 52
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 52
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 239000000203 mixture Substances 0.000 claims abstract description 82
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 36
- 239000000839 emulsion Substances 0.000 claims abstract description 34
- 239000000853 adhesive Substances 0.000 claims description 68
- 230000001070 adhesive effect Effects 0.000 claims description 68
- 150000003839 salts Chemical class 0.000 claims description 42
- AOHBGMDQHXJADT-UHFFFAOYSA-N 2-(2-dodecanoyloxypropanoyloxy)propanoic acid Chemical compound CCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C(O)=O AOHBGMDQHXJADT-UHFFFAOYSA-N 0.000 claims description 41
- 239000011159 matrix material Substances 0.000 claims description 34
- NTYZDAJPNNBYED-UHFFFAOYSA-M sodium;2-(2-dodecanoyloxypropanoyloxy)propanoate Chemical group [Na+].CCCCCCCCCCCC(=O)OC(C)C(=O)OC(C)C([O-])=O NTYZDAJPNNBYED-UHFFFAOYSA-M 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 18
- 239000011734 sodium Substances 0.000 claims description 17
- 229910052708 sodium Inorganic materials 0.000 claims description 15
- 229910052700 potassium Inorganic materials 0.000 claims description 12
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- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000002708 enhancing effect Effects 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
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- 239000013543 active substance Substances 0.000 description 4
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 4
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 4
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- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 3
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 3
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
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- 125000003118 aryl group Chemical group 0.000 description 3
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- AMJZVHHOVFFTOM-UHFFFAOYSA-M sodium;2-(2-hexanoyloxypropanoyloxy)propanoate Chemical compound [Na+].CCCCCC(=O)OC(C)C(=O)OC(C)C([O-])=O AMJZVHHOVFFTOM-UHFFFAOYSA-M 0.000 description 3
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- OZZQHCBFUVFZGT-UHFFFAOYSA-N 2-(2-hydroxypropanoyloxy)propanoic acid Chemical compound CC(O)C(=O)OC(C)C(O)=O OZZQHCBFUVFZGT-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F13/00—Bandages or dressings; Absorbent pads
- A61F13/02—Adhesive bandages or dressings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Definitions
- the present invention relates to the use of fatty acid esters of lactic acid salts as permeation enhancers in matrix patch delivery devices. More particularly, this invention relates to the use of esters of one or more fatty acids and lactic acid salts as permeation enhancers when formulated with aqueous emulsion based pressure sensitive adhesives resulting in the formation of matrix patch devices for the transdermal delivery of a wide range of active permeants.
- transdermal administration of drugs is becoming increasingly accepted as a preferred mode of delivery.
- Transdermal delivery of drugs provides many advantages over conventional oral administration. Advantages of transdermal systems include convenience, noninterrupted therapy, improved patient compliance, reversibility of treatment (by removal of the system from the skin), elimination of "hepatic first pass" effect, the high degree of control over blood concentration of any particular drug and consequent reduction of side effects.
- transdermal systems have many advantages, most drugs are not amenable to this mode of administration due to the well known barrier properties of the skin. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. The molecule must then penetrate the viable epidermis, the papillary dermis, and then the capillary walls and into systemic circulation. Along the way, each of the above mentioned tissues will exhibit a different resistance to penetration by the same molecule. However, it is the stratum corneum that presents the greatest barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum, the outer horny layer of the skin, is a complex structure of compact keratinized cell remnants separated by lipid domains. Compared to the oral or gastric mucosa, the stratum corneum is much less permeable to outside molecules.
- the flux of a drug across the skin can be increased by changing either a) the resistance (the diffusion coefficient), or b) the driving force (the solubility of the drug in the stratum corneum and consequently the gradient for diffusion).
- Many enhancer compositions have been developed to change one or more of these factors, and are known in the art.
- enhancers consisting of diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate and methyl laurate are disclosed in U.S. Pat. No. 4,973,468 as enhancing the transdermal delivery of steroids such as progestogens and estrogens.
- a dual enhancer consisting of glycerol monolaurate and ethanol for the transdermal delivery of drugs is shown in U.S. Pat. No. 4,820,720.
- U.S. Pat. No. 4,863,970 shows penetration-enhancing compositions for topical application comprising an active permeant contained in a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C 2 or C 3 alkanol and an inert diluent such as water.
- World Patent 96/37231 teaches the use of acyl lactylates as permeation enhancers for drug delivery purposes.
- This patent is specific to esters of fatty acids and lactic acid such as caproyl lactylic acid and lauroyl lactylic acid. It is stated that the salt form of acyl lactylates are not effective as permeation enhancers.
- Occlusive adhesive devices i.e. patches, for transdermal delivery of drugs is taught in U.S. Pat. Nos. 4,849,224; 4,983,395; 5,152,997 and 5,302,395. These patches are in reservoir or matrix forms as will be more fully characterized in the detailed description below.
- compositions for reducing skin irritation caused by drug/enhancer compositions having skin irritation properties comprising a percutaneously absorbable drug, a binary enhancer composition consisting of a solvent and a cell envelope disordering compound, combined with an amount of glycerin sufficient to provide an anti-irritating effect.
- Fatty acid lactylates and glycolates are known to be used as hair conditioners as shown by U.S. Pat. No. 3,728,447. Further, fatty acid lactylates and their salts, prepared from C 6 to C 22 fatty acids, are known to be used in cosmetics and have the ability to complex with skin proteins. See Murphy, et al., Acyl Lactylates in Cosmetics, D&CI (May, 1978) 35 ff and Murphy, et al., Sorption of acyl lactylates by hair and skin as documented by radio tracer studies, Cosmetics & Toiletries, 94 (March 1979) 43-49.
- Lanolinyl lactylates are shown in U.S. Pat. No. 4,422,952 to be used in water-in-oil emulsions as cosmetic supports or pharmaceutical excipients, e.g. to be used in ointments, balms, creams and the like. No physiological effect is attributed to these esters.
- U.S. Pat. No. 4,822,601 is drawn to cosmetic base compositions exhibiting therapeutic properties including sucrose fatty acid esters and fatty acid lactylates, with or without shea butter. Following application to the skin, a thickening of the epidermal layer was noted indicating a healthier and less dry skin. It was noted that topical application of such compositions also demonstrated enhanced wound healing properties and decreased sensitivity to UV light.
- compositions for enhancing the transdermal delivery of drugs which has good skin tolerability and presents minimal risks of skin toxicity or irritation.
- Another object of the invention is to provide a method of enhancing the transdermal delivery of a variety of drugs having either or both hydrophobic and hydrophilic characteristics using one or more C 6 to C 22 fatty acid esters of lactic acid salts as an enhancer when combined with aqueous emulsion based pressure sensitive adhesives.
- compositions for transdermal delivery consisting of a broad category of pharmaceutically-active agents which are lipophilic or hydrophilic, including salts, and which produce minimal or no skin irritation to human or animal tissue systems.
- the invention provides penetrating transdermal compositions based on the use of a pharmaceutically-active agent dissolved in, or admixed with, a penetration-enhancing amount of one or more C 6 to C 22 fatty acid ester of a lactic acid salt as more fully described below, in a suitable aqueous emulsion based pressure sensitive carrier vehicle. Suitable pressure sensitive adhesives will be subsequently described.
- the drug, enhancer, pressure sensitive adhesive combination is contained in an occlusive device for purposes of holding the composition against the skin or mucosa surface for administration.
- occlusive devices are generally patches for adhesion to the skin surface in matrix form.
- the invention is therefore not limited to any specific category or categories of permeants, but is inclusive of all therapeutically active compounds, and their uses to which they are responsive as more fully set forth herein.
- the invention is also inclusive of mixtures of permeants which may be administered simultaneously.
- the invention is drawn to treatment methods by means of which an effective amount of a permeant, combined with the enhancer system and pressure sensitive adhesive, is applied to the skin of a human or animal subject.
- the combination of permeant, fatty acid esters of lactic acid salts and pressure sensitive adhesive in a delivery system is preferably limited to a delivery patch in matrix form. Such patches will contain an occlusive backing.
- the terms “enhancement”, “penetration enhancement” or “permeation enhancement” relates to an increase in the permeability of the skin to a drug, so as to increase the rate at which the drug permeates through the skin.
- the enhanced permeation effected through the use of such enhancers can be observed, for example, by measuring the rate of diffusion of the drug through animal or human skin using a diffusion cell apparatus.
- the diffusion cell is described by Merritt et al. Diffusion Apparatus for Skin Penetration, J. of Controlled Release, 1 (1984) pp. 161-162.
- transdermal delivery is meant transdermal or percutaneous administration, i.e., delivery by passage of drug through the skin.
- skin i.e., skin
- stratum corneum a substance that is administered to the skin.
- stratum corneum a substance that is administered to the skin.
- stratum corneum a substance that is administered to the skin.
- percutaneous administration i.e., delivery by passage of drug through the skin.
- application situs is meant a site suitable for topical application with or without the means of a mechanical sustained release device, patch or dressing, e.g., behind the ear, on the arm, back chest, stomach, leg, top of foot, etc.
- permeant or “drug” is meant any chemical material or compound suitable for transdermal administration which includes a desired biological or pharmacological effect by application to the "application situs" for systemic delivery.
- Such substances include the broad classes of compounds normally delivered through body surfaces such as the skin.
- this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, antidiarrheal, antihistamines, anti-inflammatory agents, antimigraine preparations, antimotion sickness agents, antinauseants, antineoplastic, antiparkinsonism drugs, antipruritic, antipsychotic, antipyretics, antispasmodics including gastrointestinal and urinary, anticholinergic, sympathomimetic, xanthine derivatives, cardiovascular preparations including calcium channel blockers, beta-blockers, antiarrythmics, antihypertensives, diuretics, vasodilator including general coronary, peripheral and cerebral, central nervous system stimulants including cough and cold preparations, decongestants, diagnostics, hormones, immunosupressives, muscle relaxants, parasympatholytic
- an “effective” amount of a drug or permeant is meant a nontoxic but sufficient amount of a compound to provide the desired systemic effect.
- An “effective” amount of permeation enhancer as used herein means an amount selected so as to provide the desired increase in transdermal permeability and, correspondingly, the desired depth of penetration, rate of administration and amount of drug.
- By “effective” amount of fatty acid ester of glycolic acid or it salts or any other enhancer or carrier component is meant the amount found beneficial in a particular delivery system to achieve the desired delivery of the drug from the system.
- drug delivery system drug/enhancer composition
- drug/enhancer composition a formulated composition containing the drug to be transdermally delivered in combination with such "carriers” or “vehicles”, penetration enhancers, excipients, or any other additives.
- matrix an active permeant homogeneously combined in a biocompatible pressure sensitive adhesive which may or may not also contain other ingredients or in which the enhancer is also homogeneously dissolved or suspended.
- a matrix system is usually an occlusive adhesive patch having an impermeable film backing and, before transdermal application, a release liner on the surface of the adhesive opposite the film backing.
- a matrix system therefore is a unit dosage form of a drug composition in an adhesive carrier, also containing the enhancer and other components which are formulated for maintaining the drug composition in the adhesive in a drug transferring relationship with the derma or skin.
- Adhesive patches having non-occlusive backings are also considered to be within the scope of this definition unless specifically excluded.
- compositions of this invention require, at a minimum, a permeant capable of producing systemic effects in a carrier vehicle containing, as an enhancer, a fatty acid ester of a lactic acid salt.
- a carrier vehicle containing, as an enhancer, a fatty acid ester of a lactic acid salt.
- Such carrier vehicle is a pressure sensitive adhesive obtained from an aqueous based emulsion.
- the fatty acid esters of a lactic acid salt may be combined with other enhancers, such as cell envelope disordering compounds.
- Cell envelope disordering compounds are known in the art as being useful in topical pharmaceutical preparations. These compounds are thought to assist in skin penetration by disordering the lipid structure of the stratum corneum cell-envelopes. A representative listing of these compounds is described in the patents cited in the prior art section above which are incorporated herein by reference.
- Lactic acid salts that are useful the preparation of esters are those represented by the formula: ##STR1## where a is an integer of 1 to 4, b is 1 or 2 and M is a pharmaceutically acceptable salt forming counterion having a valency of 1 or 2.
- alkali, alkaline earth, ammonium and amine salts are suitable counterions. Representative of these are alkali metal salts such as sodium and potassium; alkaline earth metal salts such as magnesium and calcium and ammonium and amine salts.
- the amines may be primary, secondary or tertiary and may be alkyl, aryl, alkaryl and aralkyl amines.
- alkyl and alkenyl is meant any straight or branched, saturated or unsaturated, chain having from 1 to 22 carbon atoms and by aryl is meant any carbocyclic or heterocyclic group having properties of aromaticity.
- aralkyl and alkaryl is meant any combination of alkyl and aryl.
- Fatty acids used in the preparation of esters are those represented by the formula RCOOH, where R is a C 5 to C 21 alkyl or alkenyl chain which may be either straight or branched chained and which may contain hydroxy substituents. Straight C 8 to C 18 alkyl, alkenyl or hydroxy substituted alkyl or alkenyl chains are preferred.
- saturated acids, where R is alkyl are caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and the like.
- unsaturated acids where R is alkenyl
- unsaturated acids are palmitoleic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid, arachidonic acid and the like.
- Mixtures of acids, including mixtures of saturated and unsaturated acids may also be used.
- the fatty acid esters of lactic acid salts may be represented by the formula: ##STR2## where R, M, a and b are as represented above.
- M is a salt forming counterion selected from the group consisting of Na, K, Ca, Mg and ammonium or amines salts. Since these fatty acid esters of lactic acid salts are described in the prior art, further definition is not necessary. These compounds, sometimes also described as acyl lactylate salts are available from R.I.T.A. Corporation (Woodstock, Ill.) under the Pationic trade name. Some members of this class of compounds are commonly used in the food industry for their effect on bread dough properties, and other members have been used in cosmetics as emulsifiers, hair conditioners, and skin moisturizers.
- Particularly preferred fatty acid esters of lactic acid salts are members selected from the group consisting of sodium lauroyl lactylate, potassium lauroyl lactylate, sodium caproyl lactylate, sodium cocoyl lactylate, tromethamine lauroyl lactylate and the like.
- the fatty acid esters of lactic acid salts when used as enhancers may be present in an enhancer/carrier system in amounts ranging from between about 0.25 to 50% w.
- the effective amount of enhancer may vary depending on any number of factors such as the hydrophilic/hydrophobic properties of the drug, drug concentration, etc. In all systems ranges of between about 0.25 and 30% w are preferable. Most preferably the enhancer content will range between about 0.5 to 15% w regardless of the particular system.
- the adhesive is present in amounts ranging from 50 to 99.75% by weight and will preferably be present in amounts of between about 70 and 99.5% by weight.
- the enhancer is also homogeneously dissolved or suspended in the adhesive matrix and is present in amounts of between about 0.25 and 50% by weight with ranges of between about 0.5 to 30% w being preferred and 0.5 to 15% w being most preferred.
- Suitable aqueous emulsion based pressure sensitive adhesives are polymeric adhesive systems in which the adhesive polymers are suspended, emulsified, or dispersed in water forming a two-phase system.
- Suitable aqueous emulsion based pressure sensitive adhesives may include acrylic copolymer adhesives or "acrylic adhesive", (e.g. National Starch Nacor 72-9965, Monsanto Gelva 2484, Morton Morstick 214, and Rhom and Haas Robond PS-20).
- Suitable acrylic adhesives may also be prepared from emulsified acrylic dispersions (e.g. BASF Acronal A217) formulated with appropriate water-compatible or water-dispersible tackifiers such as poly(vinylmethyl ethers) (e.g.
- Suitable aqueous emulsion adhesives may also include rubber based emulsions or latexes "rubber adhesive", such as polyisobutylene or "PIB adhesive” (e.g. Lord PIB 500 or BL-100) or styrene-butadiene rubber or "SBR adhesive” (e.g. National Starch Nacor 72-8725). Rubber adhesives may also be formulated with or without water-compatible or water-dispersible tackifiers (e.g. BASF Lutonal, and Hercules Tacolyn). Suitable aqueous emulsion based pressure sensitive adhesives may also include ethylene-vinyl acetate copolymer adhesives (e.g. National Starch EVA-TACK 33-4060). However, any other suitable aqueous emulsion based pressure sensitive adhesives may also be used which are compatible with the active permeant and enhancer when utilized.
- rubber adhesive such as polyisobutylene or "PIB adhesive” (e.g
- aqueous emulsion based adhesive solutions may optionally contain thickening agents to control viscosity in amounts from 0 to 30 percent by weight.
- thickeners are present in amounts of between about 0.1 and 30 percent with amounts of 0.1 to 20 percent being preferred.
- Suitable thickening agents include hydrophilic polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy (ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran, gaur-gum, polyvinyl pyrrolidone, polyvinylpyrrolidone copolymers, pectins, starches, gelatin, casein, acrylic acid, acrylic acid esters, acrylic acid copolymers, polyacrylamides, polyurethanes, vinyl polymers, vinyl copolymers, vinyl alcohols, alkoxy polymers, polyethylene oxide polymers, polyethers, and the like.
- hydrophilic polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxy (ethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran, gaur-gum, polyvinyl pyrrolidone, polyvinylpyrrolidone copolymers, pectins, starches
- Aqueous emulsion pressure sensitive adhesives may also optionally contain defoamers, wetting agents, antioxidants, preservatives, fillers, or pigments.
- glycerin may be added as an anti-irritant or to modulate the delivery of the active permeant and may be present in amounts of from 0 to 30 percent by weight. When used, glycerin is present in amounts of between about 5 and 30 percent with amounts of 10 to 20 percent being preferred.
- the drug delivery composition may, in addition, include various agents and ingredients commonly employed in dermatological preparations. Examples are, but not limited to, fragrances, pacifiers, preservatives, anti-oxidants, and the like.
- the amount of drug present in a given composition will depend upon a variety of factors, including but not limited to, the disease or condition to be treated, the nature of the drug, the activity of the drug, the desired effect, the situs of application, possible adverse reactions, the cost and availability of the drug, solubility of the drug, and other factors within the particular knowledge of the patient and physician.
- the method of application of the present invention may vary within limits, but necessarily involves applying the selected drug composition to the skin or other tissue where drug delivery is initiated and continues at a relatively sustained rate for a period of time sufficient to provide the desired pharmacological or biological response.
- the method may involve the use of any suitable matrix type drug delivery device.
- the matrix device is brought in contact with the skin at the application situs and is held in place on the skin at the application situs by a suitable adhesive.
- Pressure sensitive adhesive matrix systems prepared according to the following steps. First, the solids content of the adhesive solution (water or organic solvent based) was determined by placing a known weight of solution in a weighed aluminum dish and evaporating the solvents overnight in a 70° C. convection oven. The solid adhesive content of the solution was calculated by dividing the adhesive solid weight after drying by the initial total solution weight. Next, a weighed quantity of adhesive solution was added to a glass bottle and the drug substance, permeation enhancer, and other excipients were weighed and added to the adhesive solution in a quantity necessary to achieve the desired dry matrix film composition. The solution containing the adhesive polymer, drug substance, and other excipients as necessary was then mixed overnight.
- the adhesive solution water or organic solvent based
- Hydroalcoholic gels were prepared on a 10 ml scale as follows. Ethyl alcohol (190 proof ethanol), water, glycerin, enhancer and drug were combined in the appropriate proportions and mixed for several hours. The gelling agent (hydroxypropylcellulose) was added and the solution was mixed briefly at high shear, then mixed at low shear until a gel was formed.
- the matrix system Prior to each permeation experiment with a matrix system, the matrix system was cut into a circular sample of 0.7 cm 2 area and the silanized release liner was removed. The adhesive was affixed to the stratum corneum side of the thawed epidermal membrane which was then cut to an appropriate size and clamped in place between the two halves of the diffusion cell with the stratum corneum facing the donor compartment.
- the receiver compartment was filled with water or an aqueous solution appropriate to maintain sink conditions for the drug. All receiver solutions included 0.02% (w/w) sodium azide (NaN 3 ) to inhibit bacterial growth.
- the diffusion cell was placed in a temperature controlled circulating water bath calibrated to maintain the surface temperature of the skin at 32° C. The receiver compartment was constantly stirred by a magnetic stir-bar in the receiver compartment agitated by a magnetic stirring module placed under the water bath.
- Permeation experiments with hydroalcoholic gels were performed using finite occluded doses.
- the occluded dose is an appropriate in vitro model for the application of a transdermal patch drug delivery system containing a liquid or gel reservoir.
- Occluded dosing experiments were set-up according to the following procedure. Prior to skin permeation experiments, the epidermal membrane was cut to an appropriate size and placed between the two halves of the diffusion cell with the epidermal side facing the receiver compartment. The receiver compartment was filled with an appropriate solution then the diffusion cell was placed in a circulating water bath calibrated to maintain the temperature of the skin surface at 32° C. and allowed to hydrate overnight. After hydration, a sample of the gel (75 ⁇ l) was pipetted into a cavity created by placing a polyethylene washer over the stratum corneum surface. This cavity was covered with an occlusive backing film which was clamped in place.
- Permeation experiments with aqueous solutions were performed using pre-saturated drug solutions containing excess drug solid (infinite dose). Prior to skin permeation experiments, the epidermal membrane was allowed to hydrate over night as described above. After hydration a well mixed sample of the aqueous solution (1 ml) was pipetted into the donor compartment formed by clamping a glass lid above the stratum corneum surface. The glass lid was then sealed with a Teflon® lined polypropylene cap.
- fatty acid esters of lactic acid salts function uniquely as enhancers when formulated from aqueous emulsion based pressure sensitive adhesives as compared to fatty acid esters of lactic acid, or even formulations of fatty acid esters of lactic acid salts as aqueous solutions, hydroalcoholic gels and solvent based pressure sensitive adhesives. Therefore the combination of an acyl lactylate salt and an aqueous emulsion pressure sensitive adhesive can be shown to be an unexpectedly and unusually effective combination for transdermal drug delivery.
- Permeation enhancement of the free acid form versus the sodium salt form of the lauroyl lactylic acid in an aqueous saturated solution was evaluated using testosterone as a model drug.
- the hydrogen ion concentration in these solutions was adjusted to pH 3 or pH 6 using a citric acid/phosphate buffer (CAPB).
- CAPB citric acid/phosphate buffer
- the control formulations show that testosterone permeation in the unenhanced formulations is not significantly affected by the pH of the aqueous buffer.
- Both the free acid and the salt form of lauroyl lactylic acid show significant permeation enhancement and the permeation enhancement of the ionized form (at pH 6) is greater than that of the unionized form (at pH 3).
- Approximately the same permeation enhancement is observed whether the starting material is the salt or the free acid indicating that when added to an aqueous solution at a fixed pH the salt and free base form of lauroyl lactylic acid are essentially equivalent. This is consistent with the expectations that free acids and their salt forms will show substantially the same results.
- Permeation enhancement of the free acid form versus the sodium salt form of the lauroyl lactylic acid using testosterone as a model drug was evaluated in a hydroalcohol gel formulation.
- the unenhanced control formulations show that testosterone permeation in the unenhanced formulations is not significantly affected by the pH of the gel.
- Both the free acid and the sodium salt form of lauroyl lactylic acid show significant permeation enhancement and the permeation enhancement of the unionized form (at pH 3) is greater than that of the ionized form (at pH 8).
- the starting material is the lauroyl lactylic acid salt or the free acid indicating that when added to a hydroalcoholic gel system at a fixed pH the salt and free acid form of lauroyl lactylic acid are virtually equivalent. This result is consistent with what might be predicted based on the interchangeability of free acids and salts.
- estradiol Permeation enhancement of the free acid form versus the sodium salt form of the lauroyl lactylic acid in a organic solvent based pressure sensitive adhesive was evaluated using estradiol as a model drug.
- An appropriate amount of estradiol was incorporated in a pressure sensitive adhesive (National Starch 2516) to achieve a dried adhesive/estradiol composition of 98.5/1.5% (w/w) (Formula 3-A).
- Comparable formulations of 1.5% estradiol and 96.5% adhesive were prepared with 2.0% lauroyl lactylic acid (Formula 3-B) or 2.0% sodium lauroyl lactylate (Formula 3-C).
- the drug and enhancer were fully dissolved in all formulations.
- the results of in vitro skin permeation experiments using these dried adhesive matrices are shown in Table 3-1.
- potassium salt form potassium lauroyl lactylate
- potassium lauroyl lactylate is also an unexpectedly effective permeation enhancer, when formulated in an emulsion based pressure sensitive adhesive.
- fatty acid lactylates of various fatty acid chain lengths were evaluated using buspirone HCl as a model compound.
- An aqueous emulsion based pressures sensitive acrylic copolymer adhesive (Nacor 72-9965, National Starch and Chemical, New Jersey) was used with buspirone HCl to prepare an unenhanced formulation at a concentration of 2% (w/w) (Formulation 6-A).
- the fatty acid lactylate salts were all obtained from R.I.T.A.
- Matrix systems were prepared with (a) 2% (w/w) clonidine HCl in 98% (w/w) of an aqueous emulsion based acrylic copolymer adhesive (Nacor 72-9965, National Starch and Chemical Company, New Jersey) (Formula 7-A), and (b) 2% (w/w) clonidine HCl in 98% (w/w) of an aqueous emulsion based ethylene-vinyl acetate copolymer adhesive (EVA-TAK 33-4060, National Starch and Chemical Company, New Jersey) (Formula 7-C), (c) an aqueous emulsion based polyisobutylene and butyl latex blended adhesive (33% BL-100, 65% PIB-500, Lord Corporation, Pompano Beach, Fla
- Enhanced formulations were prepared for comparison by adding 2.5% (w/w) of sodium lauroyl lactylate (Pationic 138C, R.I.T.A. Corporation, Woodstock, Ill.) as an enhancer and reducing the adhesive to compensate. (Formulas 7-B, 7-D, 7-F and 7-H respectively). The drug and enhancer were fully dissolved in all formulations. The results of the in vitro skin permeation for the unenhanced and enhanced systems are shown in Tables 7-1, 7-2, 7-3 and 7-4.
- sodium lauroyl lactylate was a consistently effective enhancer in all of the aqueous emulsion based matrix systems tested, increasing the permeation of clonidine about two fold over its unenhanced counterpart.
- sodium lauroyl lactylate was not an effective enhancer in the organic solvent based adhesive matrix.
- Enhanced formulations were prepared for comparison by adding 2.5% (w/w) of sodium lauroyl lactylate (Pationic 138C) as an enhancer and reducing the adhesive concentration to compensate (Formulas 8-B, 8-D and 8-F respectively). Results of in vitro skin permeation for the unenhanced and enhanced systems are shown in Tables 8-1, 8-2 and 8-3.
- Sodium lauroyl lactylate was a consistently effective enhancer in all of the matrix systems tested.
- the permeation with the system containing the acid form of diclofenac was increased about 50% by the addition of 2.5% sodium lauroyl lactylate as shown in Table 8-1, and the permeation with systems prepared from the sodium salt of diclofenac was increased by 36 to 45% in the two adhesives tested as demonstrated in Tables 8-2 and 8-3.
- Formulas 8-A and 8-B utilize a solvent based adhesive and show enhancement comparable to the aqueous emulsion based adhesive formulations of Formulas 8-C through 8-F
- a comparison of Formula 8-B with a formula containing lauroyl lactylate as a free acid instead of the salt form will show somewhat comparable results.
- a comparison of Formulas 8-D and 8-F with formulas containing lauroyl lactylate as a free acid instead of the salt form will show significant reduction in enhancement when using the free acid form.
- the above examples are but illustrative of drugs or transdermal formulations which may be employed in operation of the present invention.
- the invention is directed to the discovery that the utilization of matrix patches formed from aqueous based emulsions of pressure sensitive adhesives and fatty acid esters of lactic acid salts as defined above enhances the cumulative amount of drug delivered as compared to fatty acid esters of lactic acid, formulations of lactic acid salts with solvent based adhesives, formulation of lactic acid salts with hydroalcoholic gels, and the like. While the certain fatty acids and lactic acid salts have been primarily used for purposes of illustration other aliphatic esters of lactic acid salts may also be utilized and similar results will be realized.
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Abstract
Description
TABLE 1-1 __________________________________________________________________________ Formula 1-C Formula 1-D 2% Na Lauroyl 2% Na Lauroyl Formula 1-A Lactylate Formula 1-B Lactylate Unenhanced Unionized.sup.a Unenhanced Ionized.sup.b Skin pH3 pH3 pH6 pH6 Source Q24 Q24 E Q24 Q24 E __________________________________________________________________________ 1-I 6.9 ± 4.8 15.7 ± 1.9 2.3 7.6 ± 0.6 21.7 ± 1.6 2.9 (n =5) (n=5) (n=5) (n=5) 1-II 9.6 ± 4.1 16.5 ± 3.5 1.7 8.2 ± 3.1 30.9 ± 8.7 3.7 (n=5) (n=5) (n=5) (n=5) 1-III 18.7 ± 5.2 22.4 ± 3.8 1.2 19.0 ± 8.2 47.3 ± 2.5 2.5 (n=5) (n=5) (n=5) (n=5) All 11.7 ± 8.2 18.2 ± 3.7 1.7 ± 0.5 11.6 ± 6.4 33.3 ± 13.0 3.0 ± 0.6 Skins __________________________________________________________________________ .sup.a At this pH >97% of lauroyl lactylic acid should be present in the unionized free acid form. .sup.b At this pH >97% of lauroyl lactylic acid is present in the ionized salt form.
TABLE 1-2 __________________________________________________________________________ Formula 1-E Formula 1-F 2% Na Lauroyl 2% Na Lauroyl Formula 1-A Lactylate Formula 1-B Lactylate Unenhanced Unionized.sup.a Unenhanced Ionized.sup.b Skin pH3 pH3 pH6 pH6 Source Q24 Q24 E Q24 Q24 E __________________________________________________________________________ 1-IV 4.6 ± 0.5 9.9 ± 1.1 2.2 4.7 ± 0.9 17.7 ± 0.3 3.7 (n=5) (n=5) (n=5) (n=4) 1-V 6.5 ± 1.3 9.7 ± 1.3 1.5 5.9 ± 1.8 22.0 ± 3.1 3.7 (n=4) (n=5) (n=5) (n=5) 1-VI 18.0 ± 6.9 27.2 ± 9.2 1.5 18.0 ± 2.7 33.1 ± 7.0 1.8 (n=3) (n=4) (n=5) (n=4) All 9.7 ± 7.3 15.6 ± 10.0 1.7 ± 0.4 9.5 ± 7.4 24.3 ± 7.9 3.1 ± 1.1 Skins __________________________________________________________________________ .sup.a At this pH >97% of lauroyl lactylic acid should be present in the unionized free acid form. .sup.b At this pH >97% of lauroyl lactylic acid is present in the ionized salt form.
TABLE 2-1 __________________________________________________________________________ Formula 2-C Formula 2-D 2% Na Lauroyl 2% Na Lauroyl Formula 2-A Lactylate Formula 2-B Lactylate Unenhanced Unionized.sup.a Unenhanced Ionized.sup.b Skin pH3 pH3 pH8 pH8 Source Q24 Q24 E Q24 Q24 E __________________________________________________________________________ 2-I 129.1 ± 29.1 287.7 ± 43.5 2.2 118.5 ± 30.6 149.0 ± 42.0 1.3 (n=5) (n=5) (n=5) (n=5) 2-II 150.8 ± 21.1 372.3 ± 28.5 2.5 141.9 ± 20.0 195.6 ± 13.3 1.4 (n=5) (n=5) (n=5) (n=5) All 140.0 ± 15.3 330.0 ± 59.8 2.4 ± 0.2 130.0 ± 16.6 172.3 ± 33.0 1.4 ± 0.1 Skins __________________________________________________________________________ .sup.a At this pH >97% of lauroyl lactylic acid should be present in the unionized free acid form. .sup.b At this pH >97% of lauroyl lactylic acid is present in the ionized salt form.
TABLE 2-2 __________________________________________________________________________ Formula 2-E Formula 2-F 2% Na Lauroyl 2% Na Lauroyl Formula 2-A Lactylate Formula 2-B Lactylate Unenhanced Unionized.sup.a Unenhanced Ionized.sup.b Skin pH3 pH3 pH8 pH8 Source Q24 Q24 E Q24 Q24 E __________________________________________________________________________ 2-I 87.9 ± 22.1 173.4 ± 38.6 2.0 56.4 ± 15.4 113.5 ± 15.0 2.0 (n=5) (n=5) (n=5) (n=5) 2-II 191.3 ± 56.1 525.3 ± 74.9 2.8 179.8 ± 46.0 237.1 ± 40.3 1.3 (n=5) (n=5) (n=4) (n=5) All 139.6 ± 73.1 349.4 ± 2.4 ± 0.6 118.1 ± 87.3 175.3 ± 87.4 1.7 ± 0.5 Skins 248.8 __________________________________________________________________________ .sup.a At this pH >97% of lauroyl lactylic acid should be present in the unionized free acid form. .sup.b At this pH >97% of lauroyl lactylic acid is present in the ionized salt form.
TABLE 3-1 __________________________________________________________________________ Formula 3-B Formula 3-C Formula 3-A 2% Lauroyl 2% Na Lauroyl Skin Unenhanced Lactylic Acid Lactylate Source Q24 Q24 E Q24 E __________________________________________________________________________ 3-I 5.0 ± 1.0 7.9 ± 1.9 1.6 5.4 ± 0.9 1.1 (n=4) (n=4) (n=4) 3-II 4.7 ± 0.7 10.0 ± 1.6 2.1 6.5 ± 0.8 1.4 (n=4) (n=4) (n=4) 3-III 5.0 ± 1.1 7.2 ± 1.1 1.5 8.2 ± 0.B 1.6 (n=4) (n=4) (n=4) All 4.9 ± 0.2 8.4 ± 1.5 1.7 ± 0.4 6.7 ± 1.4 1.4 ± 0.3 Skins __________________________________________________________________________
TABLE 4-1 ______________________________________ Formula 4-A Formula 4-B Unenhanced 2% K Lauroyl Lactylate Skin Source Q24 Q24 E ______________________________________ 4-I 94.3 ± 18.8 149.8 ± 23.9 1.6 (n=5) (n=5) 4-II 57.8 ± 8.2 98.1 ± 25.7 1.7 (n=5) (n=5) 4-III 93.0 ± 8.4 148.7 ± 17.1 1.8 (n=5) (n=5) All Skins 81.7 ± 20.7 132.2 ± 29.5 16 ± 0.1 ______________________________________
TABLE 5-1 ______________________________________ Formula 5-A Formula 5-B Unenhanced 2% K Lauroyl Lactylate Skin Source Q24 Q24 E ______________________________________ 5-I 138.1 ± 7.9 117.8 ± 8.2 0.9 (n=5) (n=5) 5-II 107.1 ± 14.2 88.0 ± 14.7 0.8 (n=5) (n=5) 5-III 62.4 ± 6.8 51.7 ± 7.0 0.8 (n=5) (n=5) All Skins 102.5 ± 38.1 85.8 ± 33.7 0.8 ± 0.1 ______________________________________
TABLE 6-1 __________________________________________________________________________ Formula 6-B Formula E-C Formula 6-D Na Lauroyl (C.sub.12) Na Caproyl (C.sub.10) Na Cocoyl (C.sub.12 -C.sub.10) * Formula 6-A Lactylate Lactylate Lactylate Skin 98/2% 95.5/2/2.5% (w/w) 905/2/2.5% (w/w) 9.5/2/2.5% Source Q24 Q24 E Q24 E Q24 E __________________________________________________________________________ 6-I 18 ± 12 36 ± 18 1.9 31 ± 15 1.7 38 ± 16 2.1 (n=5) (n=5) (n=5) (n=5) 6-II 9.5 ± 5 21 ± 3 2.2 16 ± 3 1.7 13 ± 2.4 1.4 (n=5) (n=5) (n=5) (n=5) All 14 ± 10 29 ± 14 2.1 ± 0.2 23 ± 13 1.7 ± 0.04 26 ± 17 1.7 ± 5 Skins (n=10) (n=10) (n=10) (n=10) (Means) __________________________________________________________________________ *Fatty acids derived from coconut oil, mixture of C.sub.14, C.sub.12, C.sub.18 and others.
TABLE 7-1 ______________________________________ (Clonidine HC1 in Nacor 72-9965 Adhesive) Formula 7-B Formula 7-A Sodium Lauroyl Lactylate 98/2% (w/w) 95.5/2/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 7-I 12.2 ± 3.2 31.8 ± 1.3 2.6 (n=5) (n=5) 7-II 5.7 ± 2.6 9.9 ± 3.1 1.7 (n=5) (n=5) 7-III 9.1 ± 2.8 16.2 ± 8.5 1.8 (n=4) (n=5) 7-IV 7.1 ± 4.2 16.7 ± 6.4 2.3 (n=5) (n=5) All Skins 8.5 ± 3.9 18.7 ± 9.7 2.1 ± 0.4 (n=19) (n=20) ______________________________________
TABLE 7-2 ______________________________________ (Clonidine HC1 in EVA-TAK 33-4060) Formula 7-D Formula 7-C Sodium Lauroyl Lactylate 98/2% (w/w) 95.5/2/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 7-V 36.7 ± 16.8 123.5 ± 32.9 3.4 (n=5) (n=5) 7-VI 8.2 ± 5.9 20.5 ± 7.1 2.5 (n=5) (n=5) 7-VII 9.2 ± 1.5 13.2 ± 2.4 1.4 (n=3) (n=5) All Skins 19.4 ± 17.6 52.4 ± 55.1 2.4 ± 1.0 (n=13) (n=15) ______________________________________
TABLE 7-3 ______________________________________ (Clonidine HC1 in PIB/Butyl Latex Adhesive) Formula 7-F Formula 7-E Sodium Lauroyl Lactylate 33/65/2% (w/w) 32/63.5/2/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 7-VIII 13.2 ± 6.1 23.2 ± 5.9 1.8 (n=5) (n=5) 7-IX 7.2 ± 0.9 17.0 ± 2.3 2.4 (n=4) (n=4) All Skins 10.5 ± 5.3 20.5 ± 5.5 2.1 ± 0.4 (n=9) (n=9) ______________________________________
TABLE 7-4 ______________________________________ (Clonidine Base in Duro-Tak 97-2516 Adhesive) Formula 7-H Formula 7-G Sodium Lauroyl Lactylate 98.3/1.7% (w/w) 95.8/1.7/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 7-X 37.0 ± 5.1 43.8 ± 4.9 1.18 (n=5) (n=5) 7-XI 65.2 ± 27.5 49.9 ± 5.5 0.77 (n=5) (n=5) All Skins 51.1 ± 23.9 46.8 ± 5.9 0.92 ± 0.29 (n=10) (n=10) ______________________________________
TABLE 8-1 ______________________________________ (Diclofenac Acid in Durotak 87-2516 Adhesive) Formula 8-B Formula 8-A Sodium Lauroyl Lactylate 98.2/1.8% (w/w) 95.7/1.8/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 8-I 30.23 ± 3.49 38.69 ± 3.89 1.3 (n=5) (n=5) 8-II 4.13 ± 0.71 6.78 ± 1.55 1.6 (n=5) (n=5) All Skins 17.18 ± 13.96 22.73 ± 17.05 1.5 ± 0.3 (mean) (n=10) (n=10) ______________________________________
TABLE 8-2 ______________________________________ (Sodium Diclofenac in Nacor 72-9965 Adhesive) Formula 8-D Formula 8-C Sodium Lauroyl Lactylate 98/2% (w/w) 95.5/2/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 8-III 20.73 ± 1.72 27.39 ± 4.26 1.32 (n=5) (n=5) 8-IV 2.13 ± 0.44 3.39 ± 1.15 1.59 (n=5) (n=5) All Skins 11.43 ± 9.87 15.39 ± 12.98 1.45 ± 0.2 (mean) (n=10) (n=10) ______________________________________
TABLE 8-3 ______________________________________ (Sodium Diclofenac in Robond PB-20 Adhesive) Formula 8-F Formula 8-E Sodium Lauroyl Lactylate 96/2/2% (w/w) 93.5/2/2.0/2.5% (w/w) Skin Source Q24 Q24 E ______________________________________ 8-V 28.1 ± 5.4 36.8 ± 8.5 1.3 (n=5) (n=5) 8-VI 14.3 ± 6.4 19.8 ± 6.3 1.4 (n=5) (n=5) 8-VII 22.2 ± 3.8 30.5 ± 4.5 1.4 (n=5) (n=5) All Skins 21.5 ± 7.6 29.0 ± 9.5 1.36 ± 0.04 (mean) (n=15) (n=15) ______________________________________
Claims (20)
Priority Applications (1)
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US08/959,946 US5952000A (en) | 1996-10-30 | 1997-10-29 | Fatty acid esters of lactic acid salts as permeation enhancers |
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US74107196A | 1996-10-30 | 1996-10-30 | |
US08/959,946 US5952000A (en) | 1996-10-30 | 1997-10-29 | Fatty acid esters of lactic acid salts as permeation enhancers |
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---|---|---|---|
US74107196A Continuation-In-Part | 1996-10-30 | 1996-10-30 |
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US08/959,944 Expired - Lifetime US5912009A (en) | 1996-10-30 | 1997-10-29 | Fatty acid esters of glycolic acid and its salts |
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EP (2) | EP0971662A1 (en) |
JP (2) | JP2001503062A (en) |
KR (2) | KR20000035800A (en) |
CN (2) | CN1231592A (en) |
AU (2) | AU718811B2 (en) |
BR (2) | BR9712474A (en) |
CA (2) | CA2263334A1 (en) |
WO (2) | WO1998018417A1 (en) |
ZA (2) | ZA979765B (en) |
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EP0942697A1 (en) | 1999-09-22 |
JP2001503062A (en) | 2001-03-06 |
AU5157098A (en) | 1998-05-22 |
ZA979765B (en) | 1998-05-22 |
WO1998018416A1 (en) | 1998-05-07 |
BR9713492A (en) | 2000-02-29 |
US5912009A (en) | 1999-06-15 |
AU5240998A (en) | 1998-05-22 |
BR9712474A (en) | 1999-10-26 |
ZA979771B (en) | 1998-05-22 |
CA2263334A1 (en) | 1998-05-07 |
CN1231593A (en) | 1999-10-13 |
EP0971662A1 (en) | 2000-01-19 |
CN1231592A (en) | 1999-10-13 |
CA2263300A1 (en) | 1998-05-07 |
JP2001503749A (en) | 2001-03-21 |
KR20000035801A (en) | 2000-06-26 |
WO1998018417A1 (en) | 1998-05-07 |
AU717183B2 (en) | 2000-03-16 |
KR20000035800A (en) | 2000-06-26 |
AU718811B2 (en) | 2000-04-20 |
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